The control of unwanted immune responses is a critical issue in the treatment of diseases such as inflammatory diseases, autoimmune diseases, transplant rejection, allergic diseases and T cell-derived cancers. The activity of overly aggressive T cells can be controlled by immunosuppression or by the induction of immunological tolerance. Tolerance is defined as a state where the immune system is made unresponsive to an antigen, whereas immunosuppression, which decreases the immune response to antigens, usually requires the continued use of medication. In organ transplantation, T cells play an essential role in the immune response to alloantigens. Current immunosuppressive regimes commonly involve the use of corticosteroid, cyclosporin or rapamycin, which block the transcription of IL-2, a key growth factor for T cells, or inhibit IL-2 dependent proliferation. However, a number of monoclonal antibodies which either act as T cell-depleting agents (e.g. CD3, CD4, CD8), or as inhibitors of the cytokine signaling or the co-stimulatory pathways of T cells (e.g. CD25, B7-1, B7-2, CD152, CTLA4) have demonstrated effectiveness in reducing the incidence of rejection with limited side effects or toxicity. Some of these agents have been shown to have some degree of success in treating autoimmune disease and in prolonging graft survival.
Apoptosis is widely believed to be of vital importance for maintaining the proper function of the immune system and a major mechanism to remove unwanted cells (Kabelitz et al. Immunol. Today 14:338-340 (1993); Raff, Nature:356:397-399 (1992)). Various signals originating from either inside or outside a cell influence the life and death of the cell. Antibodies against T cell surface molecules such as Fas (or CD95, MW=43 kD), TNFR2 (MW=75 kD), CD2 (MW=45 kD) and CTLA-4 (MW=33 kd)) induce the apoptosis of T cells (Osborne, Curr. Opin. Immunol. 8:245-248 (1996); Lin et al. J. Immunol. 158:598-603 (1997); Zhang et al. Nature:377:348-350 (1995); Lai et al. Eur. J. Immunol. 25:3243-3248 (1995); Mollereau et al. J. Immunol. 156:3184-3190 (1996); Gribben et al. Proc. Natl. Acad. Sci. USA 92:811-815 (1995)). Attempts to use Fas and TNFR2 molecules to control unwanted T cells have been hampered by the fact that these two molecules are expressed not only on immune cells, but also on several other important organ systems like liver. This expression pattern potentially limits the therapeutic application of these two antibodies (Ogasawara et al. Nature 364:806-809 (1993); Pfeffer et al. Cell:73:457-467 (1993); Engelmann et al. J. Biological Chemistry 265:14497-14504 (1990)).
Selectins, integrins and immunoglobulin (Ig) superfamily members are three major classes of adhesion molecules that are important to the interaction of leukocytes and platelets either with themselves or with the extracellular matrix and vascular endothelium (Springer, Nature 346:425 (1990); Osborn, Cell 62:3 (1990); Hynes, Cell 69:11 (1992)). An adhesion molecule on one cell type often binds to another adhesion molecule expressed on a different cell type, forming a ligand-receptor pair.
The selectin family consists of P-selectin (also known as CD62, CD62P, GMP140, and PADGEM), E-selectin (also known as ELAM-1 and CD62E), and L-selectin (also known as LECAM-1, Mel-14, LAM-1, and CD62L). The selectins are highly homologous, composed of a 120 amino acid N-terminal lectin domain, an EGF-like domain, a variable number of multiple short consensus repeat (SCR) domains homologous to those found in complement regulatory proteins, followed by a transmembrane domain and short cytoplasmic tail (Siegelman et al., Science 243:1165-1172 (1989); Lasky et al., Cell 56:1045-1055 (1989); Tedder et al., J. Exp. Med. 170:123-133 (1989); Johnson et al., Cell 56:1033-1044 (1989); Bevilacqua et al., Proc. Natl. Acad. Sci. USA 84:9238-9242 (1987), Bevilacqua et al., Science 243:1160-1165 (1989), Bevilacqua et al., J. Clin. Invest. 91:379-387 (1993), Camerini et al., Nature 280:496-498 (1989)). The selectins have overlapping but distinct specificities for cell surface receptors (Bevilacqua et al., J. Clin. Invest. 91:379-387 (1993); Feize, Current Opinion in Struct. Biol. 3:701-710 (1993); Berg et al., Biochem. Biophys. Res. Comm. 184:1048-1055 (1992); Foxall et al., J. Cell Biol. 117:895-902 (1992); Larsen et al., J. Biol. Chem. 267:11104-11110 (1992); Polley et al., Proc. Natl. Acad. Sci. USA 88:6224-6228 (1991)).
P-selectin, E-selectin, and L-selectin mediate the first leukocyte-endothelial cell and platelet-leukocyte adhesive interactions during inflammation (Bevilacqua et al., 1993, supra). All three selectins have been demonstrated to participate in an initial “rolling” interaction of leukocytes with activated endothelium (von Andrian et al., Proc. Natl. Acad. Sci. USA 88:7538-7542 (1991); Ley et al., Blood 77:2553-2555 (1991); Abassi et al., J. Clin. Invest. 92:2719-2730 (1993); Dore et al., Blood 82:1308-1316 (1993); Jones et al., Biophys. J. 65:1560-1569 (1993); Mayadas et al., Cell 74:541-554 (1993)). P-selectin, expressed on activated platelets and endothelial cells, binds to cell surface proteins on most leukocytes (McEver et al., J. Biol. Chem. 250:9799-9804 (1984); Hsu-Lin et al., J. Biol. Chem. 264:8121-9126 (1984)). E-selectin, expressed on cytokine-activated endothelial cells (e.g., after TNF-alpha or IL-1 stimulation for 6-8 hours) binds to cell surface proteins on most leukocytes (McEver et al., J. Clin. Invest. 100:485-492 (1997); Bevilacqua et al., 1987, supra; Bevilacqua et al., 1989, supra). L-selectin, expressed on most leukocytes, binds to cell surface proteins on some endothelial cells and on other leukocytes (Gallatin et al., Nature 304:30-34 (1983); Berg et al., Immunol. Rev. 108:5-18 (1989); Berg et al., J. Cell. Biol. 114:343-349 (1991), Hallman et al., Biochem. Biophys. Res. Comm. 174:236-243 (1991); Smith et al., J. Clin. Invest. 87:609-618 (1991); Spertini et al., J. Immunol. 147:2565-2573 (1991)). All three selectins have been shown to bind to a cell surface protein, PSGL-1, whose expression is largely limited to leukocytes, and in particular T cells and NK cells. Posttranslational modifications of PSGL-1 are required for binding to P-selectin, E-selectin, and L-selectin (McEver et al., J. Clin. Invest., 1997, supra).